safety of artemisinin

8/7/2019 Safety of Artemisinin

1/28

Assessment of the safetyofartemisinin compounds

in pregnancy

Special Programme for Research & Trainingin Tropical Diseases (TDR) sponsored byU N I C E F / U N D P / W o r l d B a n k / W H O

REPORT OF TWO JOINT INFORMAL

CONSULTATIONS CONVENED IN 2006 BY:

The Special Programme for Research and

Training in Tropical Diseases (TDR) sponsored by

UNICEF/UNDP/World Bank/WHO

and

The Global Malaria Programme of the World

Health Organization


2/28


3/28

Assessment of the safety

of artemisinin compoundsin pregnancy

Report of two joint informal consultations

convened in 2006 by:

The Special Programme for Research and Training

in Tropical Diseases (TDR) sponsored by

UNICEF/UNDP/World Bank/WHO

and

The Global Malaria Programme of the World Health Organization


WHO/CDS/MAL/20903.1094WHO/GMP/TDR/Artemisinin/07.1


4/28

WHO Library Cataloguing-in-Publication Data

Assessment of the safety of artemisinin compounds in pregnancy: report of two joint informal consultations convened in

2006.

WHO/CDS/MAL/2003.1094.WHO/GMP/TDR/Artemisinin/07.1.

1.Malaria - drug therapy. 2.Artemisinins - adverse effects. 3.Pregnancy. I. The Special Programme for Research and Training

in Tropical Diseases (TDR) sponsored by UNICEF/UNDP/World Bank/WHO. 2. The Global Malaria Programme. 3.World Health

Organization

ISBN 978 92 4 159611 4 (NLM classication: QV 256)

Copyright World Health Organization on behalf of the Special Programme for Research and Training in Tropical Diseases2007All rights reserved.

The use of content from this health information product for all non-commercial education, training and information purposes is

encouraged, including translation, quotation and reproduction, in any medium, but the content must not be changed and full

acknowledgement of the source must be clearly stated. A copy of any resulting product with such content should be sent to TDR,

World Health Organization, Avenue Appia, 1211 Geneva 27, Switzerland. TDR is a World Health Organization (WHO) executed

UNICEF/UNDP/World Bank/World Health Organization Special Programme for Research and Training in Tropical Diseases.

This information product is not for sale. The use of any information or content whatsoever from it for publicity or advertising,

or for any commercial or income-generating purpose, is strictly prohibited. No elements of this information product, in part or

in whole, may be used to promote any specic individual, entity or product, in any manner whatsoever.

The designations employed and the presentation of material in this health information product, including maps and other

illustrative materials, do not imply the expression of any opinion whatsoever on the part of WHO, including TDR, the authors

or any parties cooperating in the production, concerning the legal status of any country, territory, city or area, or of its

authorities, or concerning the delineation of frontiers and borders.

Mention or depiction of any specic product or commercial enterprise does not imply endorsement or recommendation by

WHO, including TDR, the authors or any parties cooperating in the production, in preference to others of a similar nature not

mentioned or depicted.

The views expressed in this health information product are those of the authors and do not necessarily reect those of WHO,

including TDR.

WHO, including TDR, and the authors of this health information product make no warranties or representations regarding the

content, presentation, appearance, completeness or accuracy in any medium and shall not be held liable for any damages

whatsoever as a result of its use or application. WHO, including TDR, reserves the right to make updates and changes without

notice and accepts no liability for any errors or omissions in this regard. Any alteration to the original content brought about

by display or access through different media is not the responsibility of WHO, including TDR, or the authors.

WHO, including TDR, and the authors accept no responsibility whatsoever for any inaccurate advice or information that is

provided by sources reached via linkages or references to this health information product.

Printed in France


5/28

iiiAssessment of the safety of artemisinin compounds in pregnancy

TABLE OF CONTENTS

GLOSSARY ......................................................................................................................................................................................... iv

BACKGROUND..................................................................................................................................................................................... 1

EXECUTIVE SUMMARY...................................................................................................................................................................... 1

REPRODUCTIVE (PRECLINICAL) RISK ASSESSMENT OF ANTIMALARIAL THERAPY

WITH ARTEMISININ COMPOUNDS: Report of an informal consultationconvened by WHO, Geneva, January 2006....................................................................................................................................... 3

RESULTS OF RECENT ANIMAL AND IN-VITRO STUDIES ..................................................................................................................... 3Sensitive period................................................................................................................................................................................... 3Class effect........................................................................................................................................................................................... 3Comparison of species embryotoxicity in monkeys .................................................................................................................... 3

DISCUSSION OF THE EMBRYOTOXICITY OF ARTEMISININS IN PREGNANCY IN ANIMALS .............................................................. 3MECHANISM OF ACTION....................................................................................................................................................................... 4Comparison of period of sensitivity in animals and humans ......................................................................................................... 5In-vitro studies.................................................................................................................................................................................... 5Relationship to antimalarial activity................................................................................................................................................. 6

KINETICS AND METABOLISM................................................................................................................................................................ 6

COMBINATION THERAPY...................................................................................................................................................................... 6

FUTURE STUDIES .................................................................................................................................................................................. 7Experimental/animal investigations................................................................................................................................................. 7

Human investigations......................................................................................................................................................................... 7

LIST OF PARTICIPANTS......................................................................................................................................................................... 8

THE SAFETY AND EFFICACY OF ANTIMALARIAL THERAPY WITH ARTEMISININ

COMPOUNDS IN PREGNANCY:Report of an informal consultation of clinical investigatorsconvened by WHO, Geneva, October 2006 .................................................................................................................................... 11

INTRODUCTION .................................................................................................................................................................................. 11

WHO RECOMMENDATIONS................................................................................................................................................................. 11

RISK OF MALARIA INFECTION IN PREGNANCY................................................................................................................................ 12

CURRENT STUDIES ON TREATMENT OF MALARIA WITH ARTEMISININS IN PREGNANCY.............................................................. 12

DISCUSSION OF PREGNANCY REGISTRIES ....................................................................................................................................... 13Core elements of a pregnancy registry .......................................................................................................................................... 13Antiretroviral pregnancy registries ................................................................................................................................................ 13Methodological factors.................................................................................................................................................................... 13Design of Zambian Electronic Perinatal Record System (ZEPRS) Register ................................................................................ 14

PRIORITIES FOR RESEARCH .............................................................................................................................................................. 14Clinical studies.................................................................................................................................................................................. 14Randomized controlled trials (RCTs) .............................................................................................................................................. 14Observational studies ...................................................................................................................................................................... 14

INVOLVEMENT OF THE PHARMACEUTICAL INDUSTRY..................................................................................................................... 15

SUMMARY........................................................................................................................................................................................... 15

LIST OF PARTICIPANTS...................................................................................................................................................................... 16

REFERENCES....................................................................................................................................................................................... 19


6/28

iv Assessment of the safety of artemisinin compounds in pregnancy

GLOSSARY

Angioblast:alternative term for haemangioblasts.

Clonal production of primitive erythroblasts: early embryonic

red blood cells are nucleated and derived from a limited number ofhaemangioblasts in the yolk sac, so show less heterogeneity than the

later waves of blood cells from the liver.

Developmental toxicity: adverse effects on the development of the

embryo, foetus or offspring which may lead to death, abnormal growth

or abnormal structural, histological or functional development of the

offspring up to puberty.

Embryotoxicity:any adverse effect on the developing embryo

which may include death (embryolethality), malformations, growth or

functional decits.

Erythroblasts:nucleated erythrocytes.

Haemangioblasts:mesodermal cells in the yolk sac that are the

precursors of the blood cells and the blood vessels. Small groups of

haemangioblasts form blood islands in the yolk sac. These develop to

form the primitive blood cells and the endothelium of the blood vessels.

Later, haematopoiesis occurs in the liver, then the spleen and bone

marrow.

Pluripotent stem cells:stem cells capable of developing into various

types of denitive cells.

Primitive erythrocytes: earliest type of embryonic red blood cells that

contain foetal haemoglobin and a nucleus.

Primordial blood islands: see haemangioblasts.

Sensitive period: critical periods in development of an embryo

when exposure to a drug or chemical may induce particular types of

malformation. The embryo may not be sensitive to the chemical at other

times.

Teratogenicity: usually dened in the limited sense as the induction of

structural malformations in the embryo. Developmental toxicity is used

to include other types of adverse effect as dened above.

Yolk sac: early embryonic structure attached to, and outside, the

developing embryo. Source of the earliest blood cells and haematopoieticstem cells that seed the liver. Structure of the yolk sac differs in

primates and rodents. The yolk sac in rodents is inverted and completely

surrounds the embryo proper. In rodents, the large size of the yolk

sac and its close contact with the maternal blood vessels allows it to

serve an important, transient nutritive function until the denitive

chorioallantoic placenta forms around mid-gestation when embryo

development is quite advanced.

Yolk sac haematopoiesis: earliest stage of blood cell formation in the

embryo which is critical for establishing the early embryonic circulation.

Only primitive erythrocytes are formed in the yolk sac. Other blood

cell types are not formed until the liver and other embryonic sites areinitiated by haematopoietic stem cells from the yolk sac.


7/28

Assessment of the safety of artemisinin compounds in pregnancy

BACKGROUND

Artemisinins have high therapeutic value in the current clinical situation so treatment of women in early

pregnancy is inevitable. A clinician treating a febrile pregnant woman bears several possible outcomes

in mind. Failure to treat adequately may result in death or severe damage to the mother, the baby or

both. However, medicines themselves may cause toxicity and it is important that the best medicine bechosen whenever possible. Good knowledge about the actual risks of the medicine during human pregnancy

is essential in order to balance the benets against the risks.

Alone, or in combination with other antimalarials, artemisinin compounds represent a relatively new and

highly efcacious treatment and it is important to determine their safety and efcacy in pregnancy. Where

artemisinin compounds have been given during the second or third trimesters there has been no evidence

of treatment-related, adverse pregnancy outcomes. Normal outcomes have also been observed in the limited

number of pregnancies known to be exposed to artemisinin compounds in the rst trimester.

The WHO recommendation in 2003 was that artemisinin compounds cannot be recommended for treatment

of malaria in the 1st trimester. However, they should not be withheld if treatment is considered lifesaving for

the mother and other antimalarials are considered unsuitable. Because of the limited safety data, artemisinin

compounds should only be used in the 2nd and 3rd trimesters when other treatments are considered unsuitable.

This recommendation was based on the report of two informal consultations convened by WHO in 2002 (WH0,

2002).

In 2002, the mechanism of developmental toxicity in animals was not known. It was not clear whether

the initial site of action was in the mother, the foetus or on the placenta. Detailed knowledge of the

mechanism(s) involved in embryotoxicity in animals was recognized to be of value in extrapolating the risks

for humans. An informal non-clinical consultation meeting was convened in January 2006 to review the

ndings of animal studies performed since 2002 and consider their impact on the clinical use of artemisinins.

Experts in reproductive and developmental toxicity discussed new published and unpublished data on the

toxicity of artemisinins in rodents and primates. In addition, other mechanistic studies using whole embryoculture as well as isolated cells were reviewed. This meeting was followed by an informal clinical consultation

in October 2006 to discuss the safety in use of the artemisinins in early pregnancy and how to obtain more

information on safety.

EXECUTIVE SUMMARY

It was considered important for WHO to monitor the outcomes of pregnancies with early exposures to

artemisinin compounds so that any risks can be evaluated properly. The regulatory position on the minimum

number of early pregnancies necessary to increase condence about safety was that information showing

no increase in overall congenital malformation rates in at least 300 rst trimester pregnancies treated withartemisinins would demonstrate a less than tenfold increase in overall malformation risk. Information on

the absence of increased malformations in 1000 pregnancies would demonstrate a less than twofold increase

in malformation risk (EMEA, 2006). Therefore, further studies are necessary to try to achieve these numbers

of rst trimester pregnancy exposures. Current pregnancy warning labels were discussed. In the context of

malaria-endemic countries, such warnings might be of limited value if medicines are commonly used without

medical supervision. Antimalarial medicines may be used during the early stages of pregnancy without the

woman being aware she is pregnant.

Studies in animals are very valuable in indicating possible risks from medicines. Preclinical studies in rodents

have demonstrated that artemisinins can induce foetal death at high dose levels but that at lower doses

congenital malformations may be produced. The malformations can be induced in rodents only within a narrow

window in early embryogenesis. Evidence was presented that the mechanism by which embryotoxicity was

produced was through a toxic action on the very earliest developing red blood cells causing severe anaemia

in the embryo. If sufciently severe the embryos died, but in surviving embryos malformations were induced.


8/28

2 Assessment of the safety of artemisinin compounds in pregnancy

Limited data in primates, presented for the rst time at this meeting, suggest that artemisinins may have a

similar mechanism of action in the monkey leading to anaemia and embryolethality. No malformations were

observed in the primate studies but these were limited in scope.

In the rat the sensitive early red cells are produced synchronously over a very limited time period so that

a single exposure to the drug can result in a high proportion of cell deaths. In contrast, primates required

a longer period of treatment (12 days) to induce embryonic death. In humans only limited information is

available about this stage of red cell development; however it is known to take place over a longer time period

and it may well be that a limited period of treatment of two to three days for malaria would not produce such

serious toxic effects.

Following the pre-clinical meeting in 2006 the clinical meeting reviewed new data from Thailand on 1530 rst

trimester exposures to a range of antimalarial medicines including 170 treated with artemisinins. Irrespective

of the antimalarial medicine used, the higher the number of episodes of P. falciparum and the greater the

number of times the women had to be treated in the rst trimester, the greater the chance of abortion. In

addition, fever, hyperparasitaemia and older maternal age were signicant positive risk factors for an abortion

in the rst trimester, whereas antimalarial drug treatments were not signicantly related. Preliminary data

from other clinical work in progress in Zambia & Bangladesh (not yet published) were presented.

The meeting worked out the broad content of what might be achieved in the next two years. It focused

on the potential for establishing antimalarial pregnancy registries but also discussed the nature of

clinical research that might yield information on the risk-benet of treatment. Elements of the successful

collaborative Antiretroviral (ARV) Pregnancy Registry a collaboration between the United States Food

and Drug Administration (FDA), pharmaceutical industry and interested parties were discussed. The

meeting considered the registry model that could be applied to artemisinins in a similar collaborative effort.

Pharmaceutical companies indicated that they would welcome being part of such a collaboration especially

if WHO were involved. The Global Fund to Fight Aids, Tuberculosis and Malaria (GFATM) indicated their support

for such a registry, in principle.

It was concluded that there is insufcient evidence at present to warrant a change in current WHO policy

recommendations on the use of artemisinin-based products for the treatment of malaria in pregnancy. Current

WHO Guidelines (WHO Guidelines for Treatment of Malaria, 2006) recommend that in uncomplicated malaria,

artemisinin-based combination treatment should be used in the second and third trimester, but should be

used in the rst trimester only if it is the only effective treatment available. In severe malaria, artemisinins

are preferred over quinine in the second and third trimester because of the hypoglycaemia associated with

quinine. However, in the rst trimester until more evidence becomes available on the risk benet ratio of

artemisinins, both artesunate and quinine may be considered as options. In severe malaria treatment should

be started without delay and whichever medicine is immediately available should be used.


9/28


REPRODUCTIVE (PRECLINICAL) RISK ASSESSMENT OF

ANTIMALARIAL THERAPY WITH ARTEMISININ COMPOUNDS

Report of an informal consultation convened by WHO, Geneva, January 2006

RESULTS OF RECENT ANIMAL AND IN-VITRO STUDIES

There have been signicant developments in our understanding of the developmental toxicity of artemisinins

since the report of two informal consultations convened by WHO in 2002 (WHO, 2002).

Sensitive period

Developmental toxicity has been observed in rats following treatment on single days between days 10 and

14 postcoitum (pc) when artesunate was administered orally at 17 mg/kg (White et al., 2006). Day 11 pc

was the most sensitive day for the induction of embryolethality; day 10 pc was the most sensitive day for the

induction of malformations (cardiovascular defects and shortened and/or bent long bones). No developmentaltoxicity was seen following administration of the same dose administered on day 9 pc or following 30 mg/kg

on day 16 or 17 pc.

Class effect

In vivo studies (White et al., 2006) showed that four artemisinins: artesunate, dihydroartemisinin (DHA),

artemether and arteether, administered orally to pregnant rats on day 10 pc caused nearly equivalent effects

in terms of embryolethality and teratogenicity (cardiovascular defects and shortened and/or bent long bones).

This suggests that embryotoxicity (lethality and teratogenicity) is an artemisinin class effect.

Comparison of species embryotoxicity in monkeys

Previously, artemisinins had been demonstrated to be embryolethal and teratogenic in rats and rabbits.

A recent study in cynomolgus monkeys (Clark et al., 2006) found that 12 mg/kg/day and 30 mg/kg/day

artesunate treatment given on days 20 to 50 of gestation caused embryo death between days 30 and 40 of

gestation. The no-adverse-effect level was 4 mg/kg/day. No malformations were observed in four surviving

foetuses in the 12 mg/kg/day group but the sample size is not adequate to conclude that artesunate is not

teratogenic at that dose in monkeys. All three live embryos in the 30 mg/kg/day artesunate group dosed

from day 20 of gestation and removed by caesarean section on days 26, 32 and 36 of gestation respectively

had marked reductions in erythroblasts. Since embryo death was observed only after more than 12 days of

treatment, work is currently being undertaken to investigate the effects of short-term treatments to see

whether these also cause developmental toxicity.

DISCUSSION OF THE EMBRYOTOXICITY OF ARTEMISININSIN PREGNANCY IN ANIMALS

During the two-day discussion, experts in reproductive and developmental toxicity reviewed the recently

published and unpublished studies on the toxicity of artemisinins in rodents and primates outlined above.

Related studies in-vitro using whole embryo culture as well as isolated cells were also reviewed to help

elucidate the mechanism of toxic action of artemisinins in pregnancy. The following major conclusions were

agreed by the group.


10/28


MECHANISM OF ACTION

Two laboratories working independently made the same observations regarding early steps in the developmental

toxicity of artesunate. One laboratory (White et al., 2006) treated rats in vivo with artesunate and removed

embryos for examination at various intervals after treatment. The other (Longo et al., 2006) treated embryos

in whole embryo culture with DHA, the primary active metabolite of artesunate, in addition to performing in-

vivo studies. The common results demonstrated that the primary mechanism of artemisinin-induced embryo

toxicity in the rat is a sustained depletion of primitive erythrocytes (embryonic erythroblasts). There was a

marked reduction in primitive erythrocytes within 24 hours following a single dose of 17 mg/kg on day 10 or

11 pc. Embryos were viable until day 13 pc, but the majority had died by day 14 pc (White et al., 2006). It

is thought that hypoxia associated with this embryonic anaemia leads to cell death and dysmorphogenesis

including cardiovascular defects.

It was reported that the coadministration of amodiaquine ameliorates the developmental toxicity of artesunate

in rats and rabbits. It was suggested that this interaction could result from competition for binding to

haem.

The results of in-vivo and in-vitro experiments presented at this meeting suggest that the primary mechanismof artemisinin embryo toxicity in the rat is the depletion of primitive erythrocytes leading to anaemia and

hypoxia with consequent cell death. Depending upon the degree of hypoxia, the consequences for the embryo

include embryolethality and/or congenital skeletal and cardiovascular malformations. In some cases the foetus

may recover from the hypoxic event and have normal, albeit delayed, development. Congenital malformations

occur as a result of cell damage in the most sensitive organs developing at the time the hypoxia occurs. The

duration of hypoxia necessary to lead to these events is unknown, but there is a delay of three to four days

before malformations or embryonic deaths are observed. In the rat, the primitive erythrocytes are formed in

the blood islands of the yolk sac over a short period (~day 8.5-10) and begin circulating around gestational

day (GD) 10. This leads to a critical time window of sensitivity to artemisinin exposure in rats around GD 10-

14. Dosing during these days may lead to embryonic damage or death which becomes obvious by GD 13-14.

The fact that the sensitive period begins on day 10 pc suggests that the primitive erythrocytes need to be

circulating in order to be sensitive to artemisinins in vivo. The end of the sensitive period may correspond

to the time when the foetal blood cells are no longer metabolically active and cannot activate artesunate or

DHA.

In the rat, primitive erythrocyte populations arise in a clonal manner over a short time around GD 8.5-10,

being replaced by further populations of embryonic erythrocytes from GD 13. Thus, between GD 10 and

GD 13 there is a homogenous population of cells in the rat that is equally sensitive to the toxic effects of

the artemisinin compounds, leading to the profound anaemia observed. Denitive erythrocytes formed in the

liver enter the circulation by ~day 13-14 pc and are not synchronized, but produced in waves. These denitive

cells become enucleated and less metabolically active than the primitive erythrocytes. Taken together this

information suggests that if the synchronized primitive erythrocytes are killed by artemisinins, they will not

be replaced until sufcient numbers of denitive erythrocytes enter the circulation. This would explain thesustained anaemia observed after in-vivo dosing on day 10 or 11 pc. The heterogeneity provided by maturing

denitive erythrocytes could contribute to the diminution of artesunate effects after day 13 pc, as only a

subset of cells might be sensitive to artemisinin toxicity and, presumably, dead cells would be replaced by

new waves of denitive erythrocytes more rapidly than occurs during the primitive erythrocyte stage. This

is also the period when angioblasts are developing but these appear to be less sensitive to the artemisinins

since the blood vessels appear normal following low-dose exposure, though effects may be observed at higher

dose levels.

Limited data in primates (Macaca cynomolgus) presented for the rst time at this meeting suggest that the

artemisinins may have a similar mechanism of action in the monkey. Artesunate dosing during organogenesis

led to anaemia and embryolethality (Clark et al., 2006) and embryonic erythroblasts were depleted in three

live embryos in the 30 mg/kg/day group by GD 26. No malformations were observed but the limited sample

size of the primate groups studied did not allow any conclusion to be drawn as to congenital abnormalities. In


11/28


12/28


Relationship to antimalarial activity

The mechanism by which artemisinins kill malaria parasites has been studied intensely (albeit not resolved

completely). Artemisinins owe their activity to their endoperoxide bridge (two oxygens embedded in the

three-oxygen atom trioxane pharmacophore). The prevailing hypothesis is that in order for the molecule to

act as an antimalarial, it must be activated through the cleavage of the peroxide bridge. The nal target

has yet to be identied the activated artemisinin could either alkylate vital molecules or cause oxidativedamage. The activation is a one-electron transfer which requires an electron donor; this may be ferrous iron

(Fe2+), which is abundant in the parasite as haem iron (although free iron or other electron donors also may

be involved). It may be that the same processes mediate the embryotoxic effects on primitive erythrocytes.

Like the malaria parasite, primitive erythrocytes have high amounts of iron and free haem as they actively

synthesize the haem to be included in haemoglobin.

Taken together, these results indicate that the toxicity seen is likely to be a class effect (common to any

substance with an endoperoxide bridge) and species-independent. Differences in yolk sac structure and

arrangement in different species are not likely to be relevant in risk assessment.

We do not know whether, and to what extent, antimalarial activity and embryotoxicity can be divorced.

For species other than rodents, we do not know the precise time of maximum sensitivity and duration of

treatment required to induce the irreversible effects. Although the data on rst trimester exposure in humans

are very limited, it could well be that the reason why adverse effects have not been reported in humans is the

short episodic exposure to artemisinins.

KINETICS AND METABOLISM

The metabolic prole of artemisinins in all species except humans is not fully characterized. Available

data indicate much greater systemic exposure (higher plasma levels of artesunate and DHA) in humans

compared to rodents and primates. However, the in vivo dose that is effective against malarial infections is

similar among rodents, non-human primates and humans (Clark et al., 2006). Current evidence suggests thatthere may be substantial differences in metabolism and volume of distribution among species. In humans,

artesunate is metabolized to DHA, DHA-glucuronide and a THF acetate rearrangement product. In contrast,

rats have a complex metabolic prole including a number of deoxy and monohydroxylated metabolites

which are eventually eliminated as glucuronides. Moreover, in-vitro microsome work suggests that rats may

produce additional metabolites compared with humans. Taken together, this information suggests that drug

plasma concentrations of parent drug plus DHA alone may not be appropriate for risk assessment. Additional

work is needed to reconcile apparent differences in plasma concentrations and distribution proles among

experimental species and humans.

COMBINATION THERAPY

Since all artemisinins will be used in combination with other antimalarials in the treatment of uncomplicatedmalaria, the possibilities of interactions must be considered. This is especially the case where the partner

medicine has haem as the target, which may interfere with artemisinin activation. This could result

in interference with therapeutic effects as well as toxic effects so both types of interactions should be

considered.


13/28

7Assessment of the safety of artemisinin compounds in pregnancy

FUTURE STUDIES

Experimental/animal investigations

1. There is a need to understand more fully the critical period of exposure, and the duration of exposure

necessary to induce embryotoxicity in primates.

2. There is a need to perform embryotoxicity studies on newer artemisinins (synthetic trioxanes

and modied artemisinins) and other peroxidic molecules in order to evaluate their potential for

developmental toxicity.

3. There is a need for metabolic prole studies in rodents and primates to compare their proles of

metabolism with that in humans.

4. Whole embryo culture studies in vitro should be extended to investigate the role of metabolites,

oxygen and reactive species. Studies on the toxic activity of rat and human blood following artemisinin

administration would give an indication of the presence of active metabolites.

Human investigations

5. It is not known whether, in the human, clonal expansion of primitive erythroblasts occurs similarly

to that observed in rodents, leading to a period of heightened sensitivity to artemisinins. Further

work is necessary to elucidate this aspect of embryogenesis in humans.

6. There is need for a review of the safety of all antimalarial medicines in pregnancy, especially when

used during the rst trimester. In particular an up-to-date review of pregnancy outcomes following

exposure to artemisinins during the rst trimester is required urgently.

7. Since 2002, population studies have been carried out by WHO and others in Bangladesh, Kenya,

South Africa, the United Republic of Tanzania and Zambia. Some of these studies have included

exposures of pregnant women to artemisinins. These data should be made available for review

by experts in reproductive epidemiology with a view to assessing the strength of the information

involving rst-trimester exposures.

8. There is a need to establish how we can move ahead to obtain the required information about safety

in pregnancy.


14/28


LIST OF PARTICIPANTS

BECKMAN David. Novartis Pharmaceuticals Corporation, Preclinical Safety, Toxicology,

One Health Plaza, East Hanover, NJ 07936-1080, USA. Tel: +18 62 77 83 490, Fax: +19 73 78 16 339,

e-mail: [email protected].

BREWER Thomas G. Gates Foundation, Infectious Diseases, Global Health Program, PO Box 23350, Seattle,

Wa 98102, USA. Tel: 20 67 09 31 14, Fax: 20 60 93 170, e-mail: [email protected].

BROWN Nigel. St Georges Hospital Medical School, Department of Anatomy and Developmental Biology,

Cranmer Terrace, London, SW17 ORE, UK. Tel: +44 20 87 25 28 30, Fax: +44 20 87 25 07 49,


CLARK Robert. GlaxoSmithKline, UE0465, 709 Swedeland Road, King of Prussia, PA 1406-0939, USA.

Tel: 61 02 70 46 55, Fax: 61 02 70 45 42, e-mail: [email protected].

CRAFT J Carl. Medicines for Malaria Venture (MMV), International Center Cointrin, Block G, 3rd Floor,

20 Route de Pr-Bois, 1215 Geneva 15, Switzerland. Tel: +41 22 79 94 067, Fax: +41 22 79 94 061,e-mail: craf [email protected].

CROFT Simon. Drugs for Neglected Diseases Initiative (DNDi), 1 Place de Gervais, 1201 Geneva, Switzerland.

Tel: +41 22 90 69 238, Fax: +41 22 90 69 231, e-mail: [email protected].

ELEFANT Elisabeth. Centre de Renseignements sur les Agents Tratognes (CRAT), Hpital Trousseau, 26

Avenue du Dr Netter, 75012 Paris, France. Tel: 01 43 41 26 22, Fax: 01 44 73 53 97,


LONGO Monica. Nerviano Medical Sciences, 10 Viale Pasteur, 20014 Nerviano (Mi), Italy.

Tel: +39 03 31 58 12 38, Fax: +39 03 31 58 11 31, e-mail: [email protected].

MAZUE Guy. Les Fermes de Bosne, 39230 Mantry, France. Tel: +33 38 48 55 755, Fax: +33 38 48 55 742,


PIERSMA Aldert H. Laboratory for Health Effects Research RIVM, Antonie van Leeuwenhoeklaan 9,

PO Box 1, 3720 BA Bilthoven, Netherlands. Tel: 00 31 30 27 42 526, Fax: 00 31 30 27 44 446,


ROCHE Gilles. Sano-Aventis, 46 Quai de la Rape, 75601 Paris Cedex 12, France. Tel: +33 15 57 13 055,

Fax: +33 15 57 19 580, e-mail: [email protected].

SCHMUCK Gabriele. DABT Bayer HealthCare AG, PH-PD-P-T, Elberfeld, Germany. Tel: +49 20 23 68 830,Fax: +49 20 23 68 500, e-mail:[email protected].

SEILER Jrg. ToxiConSeil, Hlzlistrasse 38, 3475 Riedtwil, Switzerland. Tel: 06 29 68 17 47,

Fax: 06 29 68 17 47, e-mail: [email protected].

SULLIVAN Frank. Harrington House, 8 Harrington Road, Brighton, BN1 6RE, UK. Tel: +44 12 73 553845,

Fax: +44 12 73 500723, e-mail: [email protected].

WARD Steven. Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, L3 5QA, UK.

Tel: +44 15 17 05 32 86, Fax: +44 15 17 05 33 71, e-mail: [email protected].


15/28


WHO Secretariat

Dr Robert Ridley Director, TDR [email protected]

Dr Arata Kochi Director GMP [email protected]

Dr Andrea Bosman RBM/MSP [email protected]

Dr Mary Couper PSM/QSM

Dr Melba Gomes TDR/PDE [email protected]

Dr Tom Kanyok TDR/PDE

Dr Deborah Kioy TDR/PDE [email protected]

Dr Janis Lazdins TDR/PDE [email protected]

Dr Piero Olliaro TDR/PDE [email protected]

Dr Clive Ondari PSM/PAR

Dr Philip Onyebujoh TDR/PDE [email protected]

Dr Allan Schapira RBM/MSP


16/28


17/28


THE SAFETY AND EFFICACY OF ANTIMALARIAL THERAPY WITH

ARTEMISININ COMPOUNDS IN PREGNANCY

Report of an informal consultation of clinical investigators convened by WHO,

Geneva, October 2006

INTRODUCTION

The conclusions from preclinical studies presented in detail in the rst part of this document showed

essentially that the actions of the artemisinins are a class effect. Teratogenic effects are observed in the

absence of maternal toxicity and are limited to a narrow dose range at an early stage of embryogenesis. The

primary effect in rodents was an interference with yolk sac haematopoiesis on GD 9-14 (equivalent to weeks

2-6 in humans) that could lead to malformations or embryolethality. Studies in primates also demonstrated a

time window of sensitivity but resulted in embryolethality with no malformations being seen. It is uncertain

whether the results in animals are directly applicable to humans and whether a similar sensitive period might

exist.

From 30 October to 1 November 2006 a clinical consultation was held to address these issues by reviewing

current clinical knowledge of rst trimester risks of exposure to artemisinins in pregnancy. The meeting was

divided into three parts. Firstly, the current information on the outcome of pregnancies treated with standard

antimalarial medicines was reviewed. Secondly, these results were compared with the outcomes of pregnancy

following artemisinin use, with emphasis on rst trimester exposure. Thirdly, the use of pregnancy registries

to detect adverse effects following rst trimester exposures, and how the information obtained might be used

to inuence drug-treatment policy was discussed. The meeting also suggested future research to shed further

light on the safety of artemisinins in early pregnancy.

Malaria in pregnancy is associated with low birth weight, increased anaemia and, in low-transmission areas, an

increased risk of severe malaria. In high-transmission settings, despite the adverse effects on foetal growth,malaria is usually asymptomatic in pregnancy (Desai, 2007). There is limited information on the safety and

efcacy of most antimalarial medicines in pregnancy, particularly for exposure in the rst trimester, and so

treatment recommendations differ from those for non-pregnant adults. Organogenesis occurs mainly in the

rst trimester, therefore the time of greatest concern for potential teratogenicity, although nervous system

development continues throughout pregnancy and postnatally. Antimalarials considered safe in the rst

trimester of pregnancy are quinine, chloroquine, proguanil, pyrimethamine and sulfadoxinepyrimethamine.

Of these, quinine remains the most effective and can be used in all trimesters of pregnancy, including the

rst. In reality women often do not declare their pregnancies in the rst trimester and so early pregnancies

are often exposed inadvertently to the available rst-line treatment. Inadvertent exposure to antimalarials is

not an indication for termination of pregnancy.

WHO RECOMMENDATIONS

There is increasing experience with artemisinin derivatives in the second and third trimesters of pregnancy

(over 1000 documented cases) and no adverse effects on the mother or foetus have been reported. The current

assessment of benets and potential risks suggests that the artemisinin derivatives should be used to treat

uncomplicated falciparum malaria in the second and third trimesters of pregnancy. They should not be used

as rst-line treatment in the rst trimester until more information becomes available. Despite these many

uncertainties, effective treatment must not be delayed in seriously ill pregnant women. In practice, if rst-

line treatment with an artemisinin combination is all that is immediately available to treat pregnant women

who have symptomatic malaria in the rst trimester of pregnancy, it should be given. Pharmacovigilance

programmes to document the outcome of pregnancies exposed to artemisinin combination therapy (ACTs),and (if possible) the development of the infant, are encouraged so that future recommendations can stand

on a rmer footing.


18/28


Particularly in the second and third trimesters of pregnancy, women are more likely to develop severe

malaria. Often this is complicated by pulmonary oedema and hypoglycaemia; maternal mortality may be up to

approximately 50%, higher than in non-pregnant adults. Foetal death and premature labour are common.

Treatment of malaria in pregnancy has to be considered in two parts: uncomplicated malaria where the life

of the mother is not necessarily at risk, and severe malaria where the life of the mother is at risk and needs

to be considered as well as the life of the child. For uncomplicated malaria, current WHO Guidelines (WHO

Guidelines for Treatment of Malaria, 2006) recommend that artemisinin-based combination treatment should

be used in the second and third trimester, but should only be used in the rst trimester if it is the only

effective treatment available. In severe malaria, the artemisinins are preferred over quinine in the second

and third trimester because of the hypoglycaemia associated with quinine. However, in the rst trimester

both artesunate and quinine may be considered as options until more evidence becomes available on the

risk-benet ratio of artemisinins. Treatment should be started without delay and whichever medicine is

immediately available should be used.

RISK OF MALARIA INFECTION IN PREGNANCY

In addition to the well-known high incidence of parasites in peripheral blood in malaria in pregnancy,

there is extensive evidence of infection of the placenta, in both low- and high-transmission settings. In

high-transmission areas, primigravidae are indisputably at greater risk of infection. The gravidity effect is

less marked in low-transmission areas and absent in areas with epidemic malaria. The burden of malaria in

pregnancy is exacerbated by co-infection with HIV. Sub-Saharan Africa bears the brunt of this co-morbidity.

HIV infection seems to compromise immunity to malaria and increase the risk of malaria for mutigravidae to

equal that for primagravidae. In some areas, malaria-related mortality may occur in 1% of pregnant women,

but there is little information on malarial morbidity and mortality globally (Desai et al, 2007).

CURRENT STUDIES ON TREATMENT OF MALARIA WITH ARTEMISININSIN PREGNANCY

During this meeting, evidence was presented on artemisinin exposure in pregnancy from ongoing studies

in Thailand, Zambia and Bangladesh. Data will be published fully in due course. These studies involved

investigations on antimalarial treatments in pregnancy including rst trimester exposures. Important results

were presented from Thailand on the risk of abortion related to severity of malaria infection compared with

risks from the use of antimalarial medicines (mainly quinine, chloroquine, meoquine and artemisinin based

combinations). There was clear evidence that the risk of abortion could more than double (from around

15% to 40% or greater). The major risk factors for abortion are the number of malaria episodes with fever,

hyperparasitaemia, older maternal age and early rst trimester infection. Antimalarial treatment per se was

not associated with increased risk of abortion. Data on congenital abnormalities were insufcient to draw any

conclusions but the overall conclusion was that the risks of abortion due to malaria infection far outweighedany risks of abortion due to the use of antimalarial medicines.

The Bangladesh study treated about 3800 women, 10% of whom were pregnant, but an analysis of results was

not yet available. Very preliminary results were presented from a combined WHO-Novartis study on Coartem

being performed in Zambia. Around 500 pregnancies had been enrolled in the study of an intended 1000

pregnancies; many of the women had not yet delivered and therefore no analysis of the outcome of pregnancy

results could be made.

The evidence presented at the meeting regarding rst trimester exposures to artemisinins was reassuring but

still inadequate to warrant a change in the current WHO recommendations for treatment of malaria in rst

trimester pregnancy. Consequently, these are still valid. The medicine of choice for initial treatment in the

rst trimester of pregnancy varies because of differences in drug sensitivities in different regions. However,

because of the dangers of repeated malaria infections in pregnancy, the immediate use of artemisinins is

justied in situations where the rst treatment fails.


19/28


DISCUSSION OF PREGNANCY REGISTRIES

Core elements of a pregnancy registry

Generally, it is considered unethical to conduct clinical trials in women during the rst trimester of pregnancy

because of the risks of irreversible changes to the embryo. The use of pregnancy registries has increased in

recent years as an active method of detecting outcomes of pregnancies exposed to drugs inadvertently or

deliberately. This has been encouraged by the drug regulatory authorities as part of the post-authorization

monitoring of medicines.1

The setting up of such registries to detect adverse effects of malaria and drug exposure during pregnancy

in disease-endemic countries was discussed since inadvertent exposures to antimalarials during the rst

trimester of pregnancy will occur. Ideally, a registry should be a prospective, observational study that actively

collects information on drug exposures during pregnancy and associated pregnancy outcomes. Women with

and without exposure to the treatment of interest should be enrolled in these studies as early as possible, and

before the outcome of pregnancy is known. This avoids any bias introduced by the tendency to preferentially

report adverse outcomes.

Setting up a pregnancy registry requires pregnant women to be enrolled and data recorded on demographics,

maternal medical history, obstetrical history and details of the current pregnancy (concomitant infections,

medications [drugs, dose, route, timing of exposure] complications, severity and timing of malaria). Data

should be condential. Women need to be followed up to term and birth outcomes should be recorded:

abortion, stillbirths, live births, neonatal deaths, presence/absence of major/minor malformations and

postnatal developmental assessment. It was recognized that a study of malaria would present a number

of problems relating to the availability of medical care; multiple short-term infections; presence of HIV;

prophylactic use of antimalarials; and difculties conrming malaria and measuring the severity of infection.

A major difculty in many countries is the lack of background data on pregnancy outcomes in a normal or

unexposed population. Data from different populations with different background diseases and exposuresstrengthen understanding of drug effects.

Antiretroviral pregnancy registries

Antiretroviral medicines (ARVs) are a drug class that has been studied extensively via this method. Results

from the ARV Registry were reported at the meeting a collaborative venture between pharmaceutical

companies, regulatory authorities and interested parties. The management of this registry was passed from the

individual initiating companies to a contract research organization because of the magnitude and complexity

of the work.

Methodological factors

It is essential that the design of a prospective pregnancy register outlines what will be assessed and what

will be excluded from assessment. At its simplest the assessment of the pregnancy outcome may be limited to

recording of the vitality of the baby, its sex, birth weight and general appearance. Detection of the presence

or absence of malformations depends upon the skill and experience of the assessor (e.g. paediatrician, nurse/

midwife) and the availability of advanced diagnostic equipment. It also depends upon the age of the child

at assessment, for example cardiac malformations may not become obvious until the child is several years

old. These issues should be incorporated within the design of the study. Another problem is the denition of

comparator groups such as country- or region-specic data on pregnancy outcomes or groups treated with

other antimalarial medicines.

1 Guidance for industry: establishing pregnancy exposure registries. Available at: http://www.fda.gov/cder/guidance/3626fnl.htm,accessed 23 September 2007.European Medicines Agency. Guideline on the exposure to medicinal products during pregnancy: need for post-authorisation data(EMEA/CHMP/313666/2005). Available at: www.emea.europa.eu/pdfs/human/phvwp/31366605en.pdf, accessed 23 September 2007.


20/28


The sample size necessary to detect a signicant increase in congenital malformations depends very much

upon the frequency of the malformations and can vary from less than 100 to more than 1000 exposures.

Design of Zambian Electronic Perinatal Record System (ZEPRS) Register

An example of the setting up of a successful registry in disease-endemic countries was presented. The ZEPRS

Register is a population-based pregnancy registry recording 45 000 deliveries per annum at the University

Teaching Hospital, Lusaka. Information is recorded by midwives as part of antenatal care. This system aims

to provide basic data on birth weights, birth measurements and general aspects of pregnancy outcomes via

electronic records. Ultimately, it is hoped to include the majority of the pregnant population in Zambia so

that this registry can provide background data against which effects on pregnancy outcome from diseases and

infections (including antimalarial medicines) could be compared.

PRIORITIES FOR RESEARCH

Clinical studies

In order to hasten the acquisition of knowledge about the safety of artemisinins in early pregnancy, two

possible lines of investigation were discussed: (i) possible use of randomized controlled trials and (ii) use

of observational studies.

Randomized controlled trials (RCTs)

Generally there are major ethical barriers to the deliberate conduct of controlled drug trials in the rst

trimester of pregnancy. However, there are exceptions where the benets to the mother and foetus might

outweigh the potential disadvantages for foetal development. Two possible scenarios are detailed below.

1. It would be ethical to conduct rst trimester exposure studies in severe P. falciparum malaria where

investigation of the efcacy and safety of new drug classes would be justied in the context of

high maternal mortality. Maternal mortality would be the primary endpoint; pregnancy outcome

the secondary endpoint. For example, the safety and efcacy of intravenous artesunate could be

compared against intravenous or intramuscular quinine. Such a trial could be justied by the risk-

benet ratio. Studies should be undertaken in both south-east Asia and Africa since the outcomes

might be different.

2. Where current treatments have been demonstrated to be ineffective it would be considered ethical

to conduct an open label study to compare artemisinin-based and standard treatment for women

recrudescing from treatment for uncomplicated malaria. If rst trimester exposure was monitored,

this could provide valuable information on abortions and malformations; second- and third-trimester

exposure would provide valuable information on the incidence of low birth weight and stillbirths.

Although studies in pregnancy are difcult to perform because large sample sizes and longitudinal monitoring

would be needed for safety evaluations, nevertheless even with limited numbers of patients, valuable additional

information on kinetics and the optimum doses of the medicines can be obtained. In addition to the primary

endpoints of cure rates, other endpoints such as neonatal mortality, maternal anaemia, placental parasitaemia

and developmental delays in the offspring could be studied.

Observational studiesThe two major pregnancy-related effects of artemisinins observed in the animal studies are early pregnancy

loss and, occasionally, congenital malformations. Clinical detection of these effects is particularly difcult


21/28


as, normally, most women will not know that they are pregnant in the equivalent window of sensitivity. The

primary value of prospective observational studies would be to capture information on early pregnancy loss.

Studies could be undertaken only in communities where it is acceptable to perform early pregnancy tests.

Serum bhCG could be used to identify pregnancy and foetal age in women with severe malaria and followed,

for example, by hCG at 10 weeks to see if the women are still pregnant or foetal death has occurred. Indirect

methods to detect early foetal loss could also be used, such as intervals between pregnancies or number of

pregnancies per year.

For the detection of birth defects it is important to know the gestational age at the time of exposure to

artemisinins in pregnancy; the difculties about detecting the time of conception (discussed above) are

therefore relevant. Important design factors include the need for a control group which includes women with

exposures to other antimalarial medicines and women with none. Detection of malformations may be difcult

and dependant upon the training of assessors and the equipment available; one possibility is to include only

easily visible defects. A different approach would be the use of a retrospective case-control study design

to look at, for example, babies with cardiac defects whose mothers had malarial infections during early

pregnancy. This would enable comparisons between those treated with artemisinins, those treated with other

antimalarials and those without malarial infection.

The difculties in the conduct of these studies are not only the numbers of patients involved but also the

necessity of obtaining reliable and valid data. For example, the design and conduct of the study must be

able to detect changes in the incidence of cardiac malformations in order to remove concerns about possible

cardiac malformations. This may require a special study, employing the services of both a cardiologist and a

paediatrician with the necessary equipment, to investigate children born to women exposed to artemisinins

in early pregnancy and compare outcomes with a control unexposed population. Only by using methods

such as these will we be able to alter with condence the contraindications for early pregnancy exposure to

artemisinins.

Collaborative studies and registries in settings where artemisinins are now being deployed as rst-line

treatment are important for extending the database of pregnancies exposed to antimalarials and condence

on risks and benets of treatment. Consequently it should be of general interest that procedures are in

place to provide adequate training and monitoring to assure and maintain the quality of data. There may be

advantages in conducting smaller pilot studies to assess the feasibility of the planned work.

INVOLVEMENT OF THE PHARMACEUTICAL INDUSTRY

The manufacturers of artemisinin-based medicines and drug combinations have a responsibility for post-

marketing surveillance of their products. Representatives of these companies who were present at the meeting

expressed an interest in being involved in the investigations described above, in collaboration with WHO.

SUMMARY

The current WHO guidelines recommending the use of artemisinin combinations in the second and third

trimesters of pregnancy are supported by the increasing evidence of their safety in use. In uncomplicated

malaria, only where no other medicines are effective should the artemisinins be used in the rst trimester.

However, in severe malaria (where the mothers life is at risk) and in cases where inadequate therapy has

led to recurrent attacks, the dangers associated with the malarial disease justify the use of artemisinins in

the rst trimester. The setting up and use of pregnancy registries, clinical trials and other epidemiological

methods should be encouraged in order to increase information on the safety of artemisinins in the rst

trimester.


22/28


LIST OF PARTICIPANTS

AKHWALE Willis Head. Division of Malaria Control, Ministry of Health, 00100 GPO, P O Box 20750, Nairobi,

Kenya. Tel: +25 42 71 70 77, Fax: +25 47 13 23 4, e-mail: [email protected].

BREWER Thomas G. Bill and Melinda Gates Foundation, Infectious Diseases, Global Health Program,

PO Box 23350, Seattle, Wa 98102, USA. Tel: 20 67 09 31 14, Fax: 20 67 09 31 70,

e-mail: [email protected]. UNABLE TO ATTEND

BYARUHANGA Romano N. St Raphael of St Francis Hospital, Nsambya, PO Box 7146, Kampala, Uganda.

Tel: 25 64 12 67 012/3, Fax: 25 64 12 67 870, e-mail: [email protected].

CHUKILIZO Nditonda. Tanzania, WHO Consultant, Tanzania Food and Drugs Authority, PO Box 77150,

Dar es Salaam, Tanzania. Tel: +25 52 22 45 21 08/24 50 751, e-mail: [email protected].

CHIPIMO Miriam. (Rapporteur) Youth & HIV/AIDS, UNICEF Malawi, PO Box 30375, Lilongwe 3, Malawi.

Tel: +26 56 43 388 (cell), + 25 61 77 07 88/770/660, Fax: + 25 61 77 31 62,e-mail: [email protected].

COVINGTON Deborah. Registries & Epidemiology, Kendle International Inc., 1011 Ashes Drive, Wilmington,

NC 28405, USA. Tel: +00 19 10 50 94 904, Fax: +00 19 10 25 60 637,


FAIZ Abul. Dhaka Medical College, Dhaka-1000, Bangladesh. Tel: + 88 02 86 16 780, Fax: +

88 03 16 10 029, e-mail: [email protected], [email protected].

HOLMES Lewis Ball. Massachusetts General Hospital, Division of Genetics and Teratology, Warren Building

801, 55 Fruit Street, Boston, MA 02114-2696, USA. Tel: +61 77 26 17 42, Fax: +61 77 24 19 11,


KEMMLER Hans. Trachselwaldstrasse 1232a, CH-3452 Grnenmatt, Bern, Switzerland.

Tel: +41 34 43 11 551/+41 31 32 20 376, e-mail: [email protected].

McGREADY Rose. Shoklo Malaria Research Unit, PO Box 46, Mae Sot 63110, Thailand.


MENENDEZ Clara. International Health Centre, Hospital Clinic, Villarroel 70, E-08036 Barcelona, Spain.


MUNEENE Derrick. Global AIDS Program (GAP), American Embassy - CDC, Corner of United Nationsand Independence Avenue, PO Box 31617, Lusaka, Zambia. Tel: +26 01 25 75 15,

e-mail: [email protected] or [email protected].

MUTABINGWA T Gates. Malaria Partnership, Muheza DDH Hospital, Private Bag Muheza, Tanzania.

Tel: +255 (27) 26 41 420, Fax: +255 (27) 26 44 121, e-mail: [email protected].

NOSTEN Franois. Shoklo Malaria Research Unit (SMRU), 68/30 Ban Toong Road, PO Box 46,

Mae Sot 63110, Thailand. Tel: +66 55 54 50 21, Fax: +66 55 54 50 20, e-mail: [email protected].

RIBEIRO Isabela. Rua Verde Matas 90, Barra da Tijuca, Rio de Janeiro-RJ 22793-410, Brazil.

Tel: +55 21 24 99 60 57, e-mail: [email protected].


23/28

7Assessment of the safety of artemisinin compounds in pregnancy

SEILER J. WHO Consultant, ToxiConSeil, Hlzlistrasse 38, CH-3475 Riedtwil, Switzerland,

Tel: +41 62 96 81 747, e-mail: [email protected].

SHIELDS Mark. Global AIDS Program (GAP), American Embassy CDC, Corner of United Nations and

Independence Avenue, Lusaka, Zambia. Tel: +26 09 77 90 786, Fax: +12 02 31 84 062,

e-mail: [email protected]. UNABLE TO ATTEND

SINKALA Moses. Ministry of Health, Lusaka Urban District Management Board, Lusaka, Zambia.

Tel: +26 01 23 64 29, e-mail: [email protected].

SOFOLA TO. National RBM Coordinator, Department of Public Health, Federal Ministry of Health,

Federal Secretariat, Abuja, Nigeria. Tel: +234 (803) 30 51 149, e-mail: [email protected].

STERGACHIS Andy. Northwest Center for Public Health Practice, Interim Chair, Pathobiology, School of

Public Health & Community Medicine, University of Washington, 1107 NE 45th, Ste 400, Seattle,

WA 98105, USA. Tel: +12 06 61 69 460, Fax: +12 06 61 69 415, e-mail: [email protected].

STEKETEE Richard. MACEP, PATH, Batiment Avant Centre, 13 Chemin du Levant, 01210 Ferney Voltaire,France. Tel: +33 45 02 80 832, Fax: +33 45 02 80 407, e-mail: [email protected].

SULLIVAN Frank. Harrington House, 8 Harrington Road, Brighton, BN1 6RE, UK. Tel: 44 12 73 553845,

Fax: 44 12 73 500723, e-mail: [email protected] CHAIR, PRE-CLINICAL GROUP.

TER KUILE Feiko. Child and Reproductive Health Group, Liverpool School of Tropical Medicine,

Pembroke Place, Liverpool, L3 5QA, UK. Tel: +44 15 17 05 32 87, Fax: +44 15 17 05 33 29,


REPRESENTATION FROM PHARMACEUTICAL DEVELOPMENT

BOMPART Francois. SANOFI-AVENTIS Groupe, 46 Quai de la Rape, 75601 Paris Cedex 12, France.

Tel: +33 15 57 13 055/ +33 60 82 56 167, Fax: +33 15 57 19 580,


CRAFT J Carl. Medicines for Malaria Venture (MMV), International Center Cointrin, Block G, 3rd Floor,

20 Route de Pr-Bois, 1215 Geneva 15, Switzerland. Tel: +41 22 79 94 067, Fax: +41 22 79 94 061,


DUPARC Stephan. GlaxoSmithKline, Diseases of the Developing World, Infectious Diseases MDC,

Europe, Greenford, Middlesex UB6 0HE, UK. Tel: +44 20 89 66 52 01,


GABRIEL Silvio. Novartis Pharma AG, Lichtstrasse 35, WSJ-103.2.25, 4056 Basel, Switzerland.


IBARRA DE PALACIOS Patricia. Novartis Pharma AG, Lichtstrasse 35, WSJ-103.2.25, 4056 Basel,

Switzerland. Tel: +41 61 32 47 540, Fax: +41 61 32 46 538, e-mail: patricia.ibarra_de_palacios@

novartis.com.

LAMEYRE Valrie. SANOFI-AVENTIS, Clinical Development Groupe, 46 Quai de la Rape, 75601 Paris Cedex

12, France, Tel: +33 15 57 13 055/ +33 60 82 56 167, email: [email protected].

NAGELSCHMITZ Johannes. Bayer HealthCare AG, Clinical Pharmacology, Pharmacodynamics(PH-PD-GMD-GCP-D) Building 0429, Aprather Weg 18a, 42096 Wuppertal, Germany.

Tel: +49 20 23 68 815. email: [email protected]. UNABLE TO ATTEND


24/28


SHIN Chang Sik. Shin Poong Pharmaceutical Co. Ltd., 748-31, Yoksam-dong, Kangnam-Gu, Seoul,

Korea 135-925. Tel: 82 22 18 93 499, e-mail: [email protected].

SCHWAMLEIN Charles. Director, Global Surveillance and Pharmacoepidemiology, Abbott Laboratories,

200 Abbott Park Road, AP 34-2N, Dept 4ED, Bldg 34 2nd North, Abbott Park, IL 60064-6187, USA.

Tel: 18 47 93 80 640, e-mail: [email protected].

SCHLIENGER Raymond. Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover,

NJ 07936-1080, USA. Tel: +41 61 324 66 45, Fax: +41 61 324 84 83


SCHMIDT Albrechtgeorg. Novartis Pharma AG, Lichtstrasse 35, WSJ-103.2.25, 4056 Basel, Switzerland.


WHITE Alice. Vice President, Worldwide Epidemiology, GSK, Five Moore Drive, Research Triangle Park,

NC 27709. USA. Tel: 19 19 48 39 448, e-mail: [email protected].

WHO Secretariat

Headquarters

Dr Robert Ridley Director, TDR

Dr Arata Kochi Director, GMP

Dr Andrea Bosman GMP/CMR

Dr Mary Couper PSM/ QSM

Dr Melba Gomes TDR/PDE

Dr Tom Kanyok TDR/PDE

Dr Eline Korenromp Global Fund to Fight AIDS, Tuberculosis and MalariaDr Janis Lazdins TDR/PDE

Dr Kamini Mendis GMP/CMR

Dr Peter Olumese GMP/CMR

Dr Piero Olliaro TDR/PDE

Dr Wilson Were GMP/CMR

Dr Juliana Yartey FCM/MPS

Regional OfcesDr Magda Robalo AFRO


25/28


REFERENCES

Clark RL et al. Artesunate: developmental toxicity in monkeys. Birth Defects Research, 2006,

(Part A),76(5):329.

Desai M et al. Epidemiology and burden of malaria in pregnancy. Lancet Infect Dis, 2007, 7:93-104.

Guideline on risk assessment of medicinal products on human reproduction and lactation: from data to

labelling. European Medicines Agency, 2006 (Consultation document EMEA/CHMP/203927/2005).

Kelemen E, Calvo W, Fliedner TM.Atlas of Human Hemopoietic Development. Berlin, Springer-Verlag,

1979:20.

Lensch MW, Daley GQ. Origins of mammalian hematopoiesis: in vivo paradigms and in vitro models.

Curr. Top. Dev. Biol, 2004, 60:127-196.

Longo M et al. In vivo and in vitro investigations of the effects of the antimalarial drugdihydroartemisinin (DHA) on rat embryos. Reprod. Toxicol. 2006, 22(4):797-810.

Segel GB, Palis J. Hematology of the newborn. In: Beutler E et al., eds. Williams Hematology.

New York, McGraw-Hill, 2001:Chapter 7.

Tavian M, Peault B. The changing cellular environments of hematopoiesis in human development in

utero.Int. J. Dev. Bio, 2005, 49:243-250.

White TEK et al. Ar tesunate-induced depletion of embryonic erythroblasts precedes embryolethality

and teratogenicity in vivo. Birth Defects Research, 2006, (Part B) 77:413-429.

Assessment of the safety of artemisinin compounds in pregnancy. Report of two informal consultations

convened by WHO in 2002. Geneva, World Health Organization, 2002 (WHO/CDS/MAL/2003. 1094 2002).

WHO Guidelines for the treatment of malaria. Geneva, World Health Organization, 2006.


26/28


27/28


28/28

TDR/World Health Organization

20, Avenue Appia

1211 Geneva 27

Switzerland

Fax: (+41) 22 791-4854

[email protected]

www.who.int/tdr


The Special Programme for Research and Training in Tropical Diseases

(TDR) is a global programme of scientific collaboration established in

1975. Its focus is research into neglected diseases of the poor, with

the goal of improving existing approaches and developing new ways to

prevent, diagnose, treat and control these diseases. TDR is sponsored by

the following organizations:

ISBN 978 92 4 159611 4

safety of artemisinin

Documents